1. Field of the Invention
The present invention is directed to compositions having antiviral activity against the human cytomegalovirus ("HCMV"). More particularly, the present invention concerns pharmaceutical compositions containing the disclosed antiviral compounds which may be administered both topically and systemically.
2. Technology Review
Viruses are submicroscopic infective agents that are composed of either an RNA or a DNA core of genetic material encased in a protein shell. They are often further wrapped in lipid-containing envelopes, but they do not have a semipermeable membrane. Viruses multiply only within living cells; they commandeer the host cell to synthesize viral proteins and viral nucleic acids which are subsequently incorporated by final assembly into new virion particles.
There are various types of viral infections which may vary in severity from mild and transitory infections to illnesses that terminate in death. In lytic infections the virus replicates by inducing the cell to copy the viral genetic material and form additional virus particles. The infected cell is then lysed, releasing the virion particles. Lytic infections often spread rapidly throughout the population of vulnerable cells. The common cold and polio are examples of lytic infections.
In persistent infections, the virus does not always kill the infected cell. New virus particles are often released gradually; the cell survives intact and continues to divide, although its metabolism may undergo change. Persistent infections may also be characterized by a low level lytic infection involving only a small percentage of cells. In either case, a persistent infection may continue for months or years without causing overt disease. Hepatitis B virus, human leukemia viruses, and human immunodeficiency virus ("HIV") which is the cause of acquired immune deficiency syndrome ("AIDS"), are examples of viruses causing persistent infections.
Finally, in latent infections the genetic material of the virus can become integrated into the host cell's chromosomes which are reproduced during cell division and transmitted to the daughter cells. Under certain conditions latent viruses can be reactivated, thereby resulting in an active infection. Herpes viruses are characterized by periods of latency alternating with periods of active viral replication.
Human cytomegalovirus ("HCMV") is a member of the DNA herpes virus family. HCMV has been isolated from saliva, urine, breast milk, blood, semen, and vaginal secretions. It can be transmitted in utero, despite the presence of high maternal antibody titers. Once infected, the individual conserves the virus in a latent or persistent form throughout life.
Serological surveys indicate that most adults have been infected with HCMV. Following primary infection, which is almost always asymptomatic in people with normal immunity, the virus establishes latency. The virus is probably maintained in this latent state by immune surveillance mechanisms since immunosuppression frequently leads to reactivation of the virus. Re-infection with, or reactivation of, HCMV can give rise to life-threatening disease.
HCMV infections are manifested in a variety of disease states. Such infections in young children are often expressed as severe respiratory infection, and in older children and adults, they are expressed as anicteric hepatitis and mononucleosis. Infection with HCMV during pregnancy can lead to congenital malformation resulting in mental retardation and deafness.
HCMV pneumonitis is the most common single cause of death following bone marrow transplantation, and disseminated HCMV infection is a major cause of mortality and morbidity in patients with renal allografts or with AIDS. Recent evidence also suggests the possible role of HCMV as an oncogenic cofactor in certain tumors such as cervical carcinoma and Kaposi's sarcoma.
Like other herpes viruses, HCMV has a propensity to reactivate, particularly in immunosuppressed patients. Thus, HCMV infections present a major clinical problem for AIDS patients and other immunocompromised individuals such as organ transplant recipients and other patients receiving immunosuppressive drugs. Among AIDS patients, HCMV is the causative agent of certain invasive diseases such as retinitis, which is sight threatening, peripheral retinitis (an earlier form of the infection), and colitis.
In modern medical practice, HCMV is a significant pathogen whose ultimate control by means of immunization or drug therapy has become an important objective. So far, preliminary vaccination efforts have been unsuccessful, and no ideal therapeutic agent has been developed which can efficiently contain HCMV infection. Vaccination efforts are probably unsuccessful because the virus can infect one cell from another without being exposed to the cell milieu in which the vaccine-stimulated antibodies act. Prophylaxis and therapy using HCMV immune globulins have met with only moderate success. In addition, therapeutic agents developed for treating HCMV infections have the common disadvantages of some type of toxicity to the host and the inability to rid the host of latent infection.
A major obstacle in developing suitable drugs possessing antiviral activity against HCMV is the ability to distinguish between the virus and the patient's own cells. HCMV, like other viruses, can only replicate by physically invading a cell and using the cell's biochemical pathways to make new viral proteins and genetic material.
Because virus replication cycles are intimately connected with the functions of the host cell, there are few features peculiar to the virus that are not also present in the host. This makes selective attack on the virus difficult. Therefore, antiviral compounds generally represent a compromise between suppression of virus replication while minimizing adverse effects on the host.
Nucleoside analogs represent a major class of compounds which exhibit significant antiviral activity. These compounds are related to the naturally occurring precursors of DNA or RNA. Nucleoside analogs consist of heterocyclic bases linked to sugars or sugar-like groups.
Because nucleosides are necessary for normal DNA and RNA synthesis, certain chemically altered nucleosides interfere with the synthesis and function of DNA and/or RNA. Nucleoside analogs were first synthesized as potential anticancer drugs capable of slowing or blocking the accelerated DNA production of rapidly dividing cancer cells, but later some were found to also possess antiviral activity. Some of these compounds rapidly cross the cellular plasma membrane, thereby gaining rapid entry into the cell. Nevertheless, the cytotoxicity of nucleoside analogs remains a major drawback to their effectiveness and specificity for treating viral infections.
In discussing compositions effective against viruses, it is important to note the distinction between "antiviral" compositions and "virucidal" compositions. This distinction is most clearly understood with reference to the experimental procedures used to determine the activity.
In determining "virucidal" activity, the virus is exposed to the test composition before inoculating the tissue culture. The degree of virucidal activity is measured by comparing the quantity of virus plaques formed in tissue cultures inoculated by chemically treated virus with tissues cultures inoculated by untreated virus.
In determining "antiviral" activity, the tissue culture is inoculated with the virus and incubated for a period of time. The infected tissue culture is then treated with the test composition. The degree of antiviral activity is measured by comparing the quantity of virus plaques present in chemically treated tissue cultures with untreated tissue cultures.
Compositions that have virucidal activity do not necessarily have antiviral activity. Similarly, compositions that have virucidal or antiviral activity against one virus or even a class of viruses, do not necessarily have virucidal or antiviral activity against other viruses, even within the same class. Thus, there is a high degree of unpredictability in both the mode of activity and virus selectivity for virucidal and antiviral compositions.
Compositions having virucidal activity are particularly important as topical disinfectants. In general, virucidal compositions have doubtful usefulness in treating patients already infected with a virus. In contrast, antiviral compositions are primarily used to treat patients having existing viral infections.
Of the known antiviral agents, foscarnet, acyclovir, and ganciclovir (shown below) are presently undergoing clinical evaluation for effectiveness in the treatment of HCMV infections in AIDS patients. ##STR2##
Ganciclovir, a nucleoside derivative also known as "DHPG", has been approved to treat HCMV retinitis in individuals with AIDS based on the positive effects seen in short term clinical trials. Although this represents encouraging progress in the treatment of HCMV infections, ganciclovir is not an ideal chemotherapeutic agent. The drug possesses serious toxic side effects such as neutropenia (an abnormally small number of neutrophil cells in the blood) which will preclude use of ganciclovir in an estimated 40% of all AIDS HCMV patients. Recently, ganciclovir-resistent mutant viral strains have been reported in AIDS patients treated with the drug and have been associated with severe progression of the disease.
From the foregoing, it will be appreciated that what is needed in the art are active pharmaceutical compositions having novel antiviral activity against HCMV and methods of administering said compositions.
In addition, it would be a significant advancement in the art to provide non-nucleoside antiviral compositions and methods of administering said compositions which specifically attack HCMV without substantially inhibiting normal cellular metabolism.
Such antiviral compositions and administration methods are disclosed and claimed herein.